High school: Scientific bilingual school (english and german)
University: Master degree in pharmaceutical and medical biotechnology
Activity after degree: PhD in Molecular Medicine
RESEARCH INTERESTS
Cardiovascular pathologies, hypertrophic cardiomyopathy, induced pluripotent stem cells derived cardiomyocytes, pharmacological therapies, human samples from surgical myectomies, gaining insights into pathomechanisms oh hypertrophic cardiomyopathy, arrhythmogenesis
21
Scopus Publications
Scopus Publications
Beat-to-beat variability of ventricular repolarization reveals sex-specific instability and proarrhythmic risk Daisuke Sato, Lorenzo Santini, Raffaele Coppini, Eleonora Grandi Journal of Physiology, 2026 Beat‐to‐beat QT interval variability (QTV) is a well‐established marker of increased vulnerability to ventricular arrhythmias; however the underlying electrophysiological mechanisms remain poorly understood. In this study, we employed sex‐specific, physiologically detailed computational models of human ventricular myocytes to investigate the role of dynamical repolarization instability under baseline and pharmacologically perturbed conditions. Action potential duration (APD) variability was quantified as a cellular‐level surrogate for QTV and evaluated in relation to restitution kinetics, drug risk classification and biological sex. Female models exhibited significantly greater APD variability than male models, consistent with clinical observations of sex differences in QTV. Exposure to high‐risk torsadogenic compounds further amplified APD variability, whereas drugs with low proarrhythmic potential produced only modest effects. Intermediate‐risk agents elicited APD variability patterns aligned with previously reported machine learning–based predictions of torsades de pointes (TdP) risk. Notably increased APD variability strongly correlated with steeper APD restitution slopes, reflecting enhanced dynamical instability. Importantly elevated variability was observed even in the absence of early afterdepolarizations (EADs), underscoring its potential as a sensitive, early marker of proarrhythmic susceptibility. These findings provide mechanistic evidence linking dynamical instability to QTV and establish sex as a critical modulator of arrhythmogenic drug response. image Key points Beat‐to‐beat QT interval variability (QTV) is an established clinical marker of arrhythmic risk, but the mechanistic link between QTV and arrhythmia remains poorly understood. Using sex‐specific, physiologically detailed human ventricular myocyte models, we show that QTV arises from dynamical repolarization instability, with action potential duration (APD) variability closely tracking the slope of the APD restitution curve. Female models exhibited greater baseline APD variability than male models, in agreement with findings in human ventricular cardiomyocyte experiments, and exposure to high‐risk torsadogenic drugs further amplified this variability in a concentration‐dependent manner, even in the absence of early afterdepolarizations (EADs). APD variability emerged as an indicator of dynamical instability and was predictive of arrhythmogenic susceptibility across a range of pacing rates and pharmacological conditions. Our findings support its integration into safety pharmacology frameworks to improve current arrhythmia risk assessment.
Obscurin deficiency leads to compensated dilated cardiomyopathy and increased arrhythmias Josè Manuel Pioner, Enrico Pierantozzi, Raffaele Coppini, Egidio Maria Rubino, Valentina Biasci, Giulia Vitale, Annunziatina Laurino, Lorenzo Santini, Marina Scardigli, Davide Randazzo, Camilla Olianti, Matteo Serano, Daniela Rossi, Chiara Tesi, Elisabetta Cerbai, Stephan Lange, Carlo Reggiani, Leonardo Sacconi, Corrado Poggesi, Cecilia Ferrantini, Vincenzo Sorrentino Journal of General Physiology, 2025 Obscurin is a large muscle protein whose multiple functions include providing mechanical strength to the M-band and linking the sarcomere to the sarcoplasmic reticulum. Mutations in obscurin are linked to various forms of muscle diseases. This study compares cardiac function in a murine model of obscurin deletion (KO) with wild-type (WT) in vivo and ex vivo. Echocardiography showed that KO hearts had larger (+20%) end-diastolic and end-systolic volumes, reduced fractional shortening, and impaired ejection fraction, consistent with dilated cardiomyopathy. However, stroke volume and cardiac output were preserved due to increased end-diastolic volume. Morphological analyses revealed reduced sarcoplasmic reticulum volume, with preserved T-tubule network. While myofilament function was preserved in isolated myofibrils and skinned trabeculae, experiments in intact trabeculae revealed that Obscn KO hearts compared with WT displayed (1) reduced active tension at high frequencies and during resting-state contractions, (2) impaired positive inotropic and lusitropic response to β-adrenergic stimulation (isoproterenol 0.1 μM), and (3) faster mechanical restitution, suggesting reduced sarcoplasmic reticulum refractoriness. Intracellular [Ca2+]i measurements showed reduced peak systolic and increased diastolic levels in KO versus WT cardiomyocytes. Western blot experiments revealed lower SERCA and phospholamban (PLB) expression and reduced PLB phosphorylation in KO mice. While action potential parameters and conduction velocity were unchanged, β-adrenergic stimulation induced more frequent spontaneous Ca2+ waves and increased arrhythmia susceptibility in KO compared with WT. Taken together, these findings suggest that obscurin deletion, in adult mice, is linked to compensated dilated cardiomyopathy, altered E-C coupling, impaired response to inotropic agents, and increased propensity to arrhythmias.
Optogenetic confirmation of transverse-tubular membrane excitability in intact cardiac myocytes Marina Scardigli, Michal Pásek, Lorenzo Santini, Chiara Palandri, Emilia Conti, Claudia Crocini, Marina Campione, Leslie M. Loew, Antoine A. F. de Vries, Daniël A. Pijnappels, Francesco S. Pavone, Corrado Poggesi, Elisabetta Cerbai, Raffaele Coppini, Peter Kohl, Cecilia Ferrantini, Leonardo Sacconi Journal of Physiology, 2024 T‐tubules (TT) form a complex network of sarcolemmal membrane invaginations, essential for well‐co‐ordinated excitation–contraction coupling (ECC) and thus homogeneous mechanical activation of cardiomyocytes. ECC is initiated by rapid depolarization of the sarcolemmal membrane. Whether TT membrane depolarization is active (local generation of action potentials; AP) or passive (following depolarization of the outer cell surface sarcolemma; SS) has not been experimentally validated in cardiomyocytes. Based on the assessment of ion flux pathways needed for AP generation, we hypothesize that TT are excitable. We therefore explored TT excitability experimentally, using an all‐optical approach to stimulate and record trans‐membrane potential changes in TT that were structurally disconnected, and hence electrically insulated, from the SS membrane by transient osmotic shock. Our results establish that cardiomyocyte TT can generate AP. These AP show electrical features that differ substantially from those observed in SS, consistent with differences in the density of ion channels and transporters in the two different membrane domains. We propose that TT‐generated AP represent a safety mechanism for TT AP propagation and ECC, which may be particularly relevant in pathophysiological settings where morpho‐functional changes reduce the electrical connectivity between SS and TT membranes. imageKey points Cardiomyocytes are characterized by a complex network of membrane invaginations (the T‐tubular system) that propagate action potentials to the core of the cell, causing uniform excitation–contraction coupling across the cell. In the present study, we investigated whether the T‐tubular system is able to generate action potentials autonomously, rather than following depolarization of the outer cell surface sarcolemma. For this purpose, we developed a fully optical platform to probe and manipulate the electrical dynamics of subcellular membrane domains. Our findings demonstrate that T‐tubules are intrinsically excitable, revealing distinct characteristics of self‐generated T‐tubular action potentials. This active electrical capability would protect cells from voltage drops potentially occurring within the T‐tubular network.
Slower Calcium Handling Balances Faster Cross-Bridge Cycling in Human MYBPC3 HCM Josè Manuel Pioner, Giulia Vitale, Sonette Steczina, Marianna Langione, Francesca Margara, Lorenzo Santini, Francesco Giardini, Erica Lazzeri, Nicoletta Piroddi, Beatrice Scellini, Chiara Palandri, Maike Schuldt, Valentina Spinelli, Francesca Girolami, Francesco Mazzarotto, Jolanda van der Velden, Elisabetta Cerbai, Chiara Tesi, Iacopo Olivotto, Alfonso Bueno-Orovio, Leonardo Sacconi, Raffaele Coppini, Cecilia Ferrantini, Michael Regnier, Corrado Poggesi Circulation Research, 2023 Background: The pathogenesis of MYBPC3 -associated hypertrophic cardiomyopathy (HCM) is still unresolved. In our HCM patient cohort, a large and well-characterized population carrying the MYBPC3 :c772G>A variant (p.Glu258Lys, E258K) provides the unique opportunity to study the basic mechanisms of MYBPC3 -HCM with a comprehensive translational approach. Methods: We collected clinical and genetic data from 93 HCM patients carrying the MYBPC3 :c772G>A variant. Functional perturbations were investigated using different biophysical techniques in left ventricular samples from 4 patients who underwent myectomy for refractory outflow obstruction, compared with samples from non-failing non-hypertrophic surgical patients and healthy donors. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and engineered heart tissues (EHTs) were also investigated. Results: Haplotype analysis revealed MYBPC3 :c772G>A as a founder mutation in Tuscany. In ventricular myocardium, the mutation leads to reduced cMyBP-C (cardiac myosin binding protein-C) expression, supporting haploinsufficiency as the main primary disease mechanism. Mechanical studies in single myofibrils and permeabilized muscle strips highlighted faster cross-bridge cycling, and higher energy cost of tension generation. A novel approach based on tissue clearing and advanced optical microscopy supported the idea that the sarcomere energetics dysfunction is intrinsically related with the reduction in cMyBP-C. Studies in single cardiomyocytes (native and hiPSC-derived), intact trabeculae and hiPSC-EHTs revealed prolonged action potentials, slower Ca 2+ transients and preserved twitch duration, suggesting that the slower excitation-contraction coupling counterbalanced the faster sarcomere kinetics. This conclusion was strengthened by in silico simulations. Conclusions: HCM-related MYBPC3 :c772G>A mutation invariably impairs sarcomere energetics and cross-bridge cycling. Compensatory electrophysiological changes (eg, reduced potassium channel expression) appear to preserve twitch contraction parameters, but may expose patients to greater arrhythmic propensity and disease progression. Therapeutic approaches correcting the primary sarcomeric defects may prevent secondary cardiomyocyte remodeling.
Cardiac safety assessment of a novel recombinant bispecific antibody targeting the ether-à-go-go related gene 1 (hERG1)-β1 integrin macromolecular complex Lorenzo Santini, Claudia Duranti, Chiara Palandri, Lucrezia Giammarino, Monica Musumeci, Lucia Carlucci, Chiara Capitani, Rossella Colasurdo, Fabio Recchia, Elisabetta Cerbai, Raffaele Coppini, Annarosa Arcangeli Frontiers in Pharmacology, 2023 Introduction: In the last decades, mounting evidence has pointed out the human ether-á-go-go–related gene (hERG1) potassium channel as a novel biomarker in human cancers. However, hERG1 sustains the cardiac repolarizing current IKr and its blockade can induce a prolonged QT interval at the ECG, which increases the risk of life-threatening arrhythmias. This represents a major hindrance for targeting hERG1 for antineoplastic therapeutic purposes. Based on our discovery that hERG1 resides in a macromolecular complex with the β1 subunit of integrin adhesion receptors only in tumors, and not in the heart, we generated (and patented WO2019/015936) a novel engineered, single chain, bispecific antibody in the format of a diabody (scDb-hERG1-β1). This antibody has been proven to target with high affinity the hERG1/β1 integrin complex and to exert a good antineoplastic activity in preclinical mouse models.Methods: In the present study, we evaluated the cardiac safety of the scDb-hERG1-β1, determining the action potential duration (APD) of human cardiomyocytes, either atrial (from valve-disease patients) or ventricular (from aortic stenosis patients). Cardiac cells were incubated in vitro with i) the scDb-hERG1-β1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDb-hERG1-β1 was assembled. All the tests were performed before and after treatment with the specific hERG1 blocker E4031. In addition, we have performed preliminary experiments, analyzing the effects of the scDb-hERG1/β1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs.Results: The scDb-hERG1-β1 did not produce any lengthening of APD compared to control (vehicle) conditions, either in atrial or ventricular cardiomyocytes, whereas both the hERG1-mAb and the scFv-hERG1 produced a significant APD prolongation. The addition of E4031 further prolonged APD. The scDb-hERG1-β1 did not produce any alterations of the QT (and QTc) interval values, once injected intravenously in farm pigs.Discussion: Overall, the above evidences plead for the cardiac safety of the scDb-hERG1-β1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.
Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms V. Biasci, L. Santini, G. A. Marchal, S. Hussaini, C. Ferrantini, R. Coppini, L. M. Loew, S. Luther, M. Campione, C. Poggesi, F. S. Pavone, E. Cerbai, G. Bub, L. Sacconi Basic Research in Cardiology, 2022 Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel recovery and intracellular Ca2+ cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics. We investigated the effects of sub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressing a light-gated ion channel (channelrhodopsin-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs and reduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects the dynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We used an optical system that uses real-time feedback control to generate re-entrant circuits with user-defined cycle lengths to explore the role of cardiac alternans in spontaneous termination of ventricular tachycardias (VTs). We demonstrate that VT stability significantly decreases during sub-threshold illumination primarily due to an increase in the amplitude of electrical oscillations, which implies that cardiac alternans may be beneficial in the context of self-termination of VT.
Calcium handling maturation and adaptation to increased substrate stiffness in human iPSC-derived cardiomyocytes: The impact of full-length dystrophin deficiency Josè Manuel Pioner, Lorenzo Santini, Chiara Palandri, Marianna Langione, Bruno Grandinetti, Silvia Querceto, Daniele Martella, Costanza Mazzantini, Beatrice Scellini, Lucrezia Giammarino, Flavia Lupi, Francesco Mazzarotto, Aoife Gowran, Davide Rovina, Rosaria Santoro, Giulio Pompilio, Chiara Tesi, Camilla Parmeggiani, Michael Regnier, Elisabetta Cerbai, David L. Mack, Corrado Poggesi, Cecilia Ferrantini, Raffaele Coppini Frontiers in Physiology, 2022 Cardiomyocytes differentiated from human induced Pluripotent Stem Cells (hiPSC- CMs) are a unique source for modelling inherited cardiomyopathies. In particular, the possibility of observing maturation processes in a simple culture dish opens novel perspectives in the study of early-disease defects caused by genetic mutations before the onset of clinical manifestations. For instance, calcium handling abnormalities are considered as a leading cause of cardiomyocyte dysfunction in several genetic-based dilated cardiomyopathies, including rare types such as Duchenne Muscular Dystrophy (DMD)-associated cardiomyopathy. To better define the maturation of calcium handling we simultaneously measured action potential and calcium transients (Ca-Ts) using fluorescent indicators at specific time points. We combined micropatterned substrates with long-term cultures to improve maturation of hiPSC-CMs (60, 75 or 90 days post-differentiation). Control-(hiPSC)-CMs displayed increased maturation over time (90 vs 60 days), with longer action potential duration (APD), increased Ca-T amplitude, faster Ca-T rise (time to peak) and Ca-T decay (RT50). The progressively increased contribution of the SR to Ca release (estimated by post-rest potentiation or Caffeine-induced Ca-Ts) appeared as the main determinant of the progressive rise of Ca-T amplitude during maturation. As an example of severe cardiomyopathy with early onset, we compared hiPSC-CMs generated from a DMD patient (DMD-ΔExon50) and a CRISPR-Cas9 genome edited cell line isogenic to the healthy control with deletion of a G base at position 263 of the DMD gene (c.263delG-CMs). In DMD-hiPSC-CMs, changes of Ca-Ts during maturation were less pronounced: indeed, DMD cells at 90 days showed reduced Ca-T amplitude and faster Ca-T rise and RT50, as compared with control hiPSC-CMs. Caffeine-Ca-T was reduced in amplitude and had a slower time course, suggesting lower SR calcium content and NCX function in DMD vs control cells. Nonetheless, the inotropic and lusitropic responses to forskolin were preserved. CRISPR-induced c.263delG-CM line recapitulated the same developmental calcium handling alterations observed in DMD-CMs. We then tested the effects of micropatterned substrates with higher stiffness. In control hiPSC-CMs, higher stiffness leads to higher amplitude of Ca-T with faster decay kinetics. In hiPSC-CMs lacking full-length dystrophin, however, stiffer substrates did not modify Ca-Ts but only led to higher SR Ca content. These findings highlighted the inability of dystrophin-deficient cardiomyocytes to adjust their calcium homeostasis in response to increases of extracellular matrix stiffness, which suggests a mechanism occurring during the physiological and pathological development (i.e. fibrosis).
Pharmacological Management of Hypertrophic Cardiomyopathy: From Bench to Bedside Chiara Palandri, Lorenzo Santini, Alessia Argirò, Francesca Margara, Ruben Doste, Alfonso Bueno-Orovio, Iacopo Olivotto, Raffaele Coppini Drugs, 2022 Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is still orphan of a specific drug treatment. The erroneous consideration of HCM as a rare disease has hampered the design and conduct of large, randomized trials in the last 50 years, and most of the indications in the current guidelines are derived from small non-randomized studies, case series, or simply from the consensus of experts. Guideline-directed therapy of HCM includes non-selective drugs such as disopyramide, non-dihydropyridine calcium channel blockers, or β-adrenergic receptor blockers, mainly used in patients with symptomatic obstruction of the outflow tract. Following promising preclinical studies, several drugs acting on potential HCM-specific targets were tested in patients. Despite the huge efforts, none of these studies was able to change clinical practice for HCM patients, because tested drugs were proven to be scarcely effective or hardly tolerated in patients. However, novel compounds have been developed in recent years specifically for HCM, addressing myocardial hypercontractility and altered energetics in a direct manner, through allosteric inhibition of myosin. In this paper, we will critically review the use of different classes of drugs in HCM patients, starting from "old" established agents up to novel selective drugs that have been recently trialed in patients.
Paradoxical prolongation of QT interval during exercise in patients with hypertrophic cardiomyopathy: cellular mechanisms and implications for diastolic function Raffaele Coppini, Matteo Beltrami, Ruben Doste, Alfonso Bueno-Orovio, Cecilia Ferrantini, Giulia Vitale, Josè Manuel Pioner, Lorenzo Santini, Alessia Argirò, Martina Berteotti, Fabio Mori, Niccolò Marchionni, Pierluigi Stefàno, Elisabetta Cerbai, Corrado Poggesi, Iacopo Olivotto European Heart Journal Open, 2022 Aims Ventricular cardiomyocytes from hypertrophic cardiomyopathy (HCM) patient hearts show prolonged action potential duration (APD), impaired intracellular Ca2+ homeostasis and abnormal electrical response to beta -adrenergic stimulation. We sought to determine whether this behaviour is associated with abnormal changes of repolarization during exercise and worsening of diastolic function, ultimately explaining the intolerance to exercise experienced by some patients without obstruction. Methods and results Non-obstructive HCM patients (178) and control subjects (81) underwent standard exercise testing, including exercise echocardiography. Ventricular myocytes were isolated from myocardial samples of 23 HCM and eight non-failing non-hypertrophic surgical patients. The APD shortening in response to high frequencies was maintained in HCM myocytes, while β-adrenergic stimulation unexpectedly prolonged APDs, ultimately leading to a lesser shortening of APDs in response to exercise. In HCM vs. control subjects, we observed a lesser shortening of QT interval at peak exercise (QTc: +27 ± 52 ms in HCM, −4 ± 50 ms in controls, P < 0.0001). In patients showing a marked QTc prolongation (>30 ms), the excessive shortening of the electrical diastolic period was linked with a limited increase of heart-rate and deterioration of diastolic function at peak effort. Conclusions Abnormal balance of Ca2+- and K+-currents in HCM cardiomyocytes determines insufficient APD and Ca2+-transient shortening with exercise. In HCM patients, exercise-induced QTc prolongation was associated with impaired diastolic reserve, contributing to the reduced exercise tolerance. Our results support the idea that severe electrical cardiomyocyte abnormalities underlie exercise intolerance in a subgroup of HCM patients without obstruction.
Optical investigation of action potential and calcium handling maturation of hiPSC-cardiomyocytes on biomimetic substrates Josè Manuel Pioner, Lorenzo Santini, Chiara Palandri, Daniele Martella, Flavia Lupi, Marianna Langione, Silvia Querceto, Bruno Grandinetti, Valentina Balducci, Patrizia Benzoni, Sara Landi, Andrea Barbuti, Federico Ferrarese Lupi, Luca Boarino, Laura Sartiani, Chiara Tesi, David L. Mack, Michael Regnier, Elisabetta Cerbai, Camilla Parmeggiani, Corrado Poggesi, Cecilia Ferrantini, Raffaele Coppini International Journal of Molecular Sciences, 2019
Liquid Crystalline Networks toward Regenerative Medicine and Tissue Repair Daniele Martella, Paolo Paoli, Josè M. Pioner, Leonardo Sacconi, Raffaele Coppini, Lorenzo Santini, Matteo Lulli, Elisabetta Cerbai, Diederik S. Wiersma, Corrado Poggesi, Cecilia Ferrantini, Camilla Parmeggiani Small, 2017
Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction Donato Cappetta, Grazia Esposito, Raffaele Coppini, Elena Piegari, Rosa Russo, Loreta Pia Ciuffreda, Alessia Rivellino, Lorenzo Santini, Concetta Rafaniello, Cristina Scavone, Francesco Rossi, Liberato Berrino, Konrad Urbanek, Antonella De Angelis British Journal of Pharmacology, 2017
